8p2m
C. elegans TIR-1 protein.
Structural highlights
FunctionSARM1_CAEEL NAD(+) hydrolase, which plays a key role in non-apoptotic cell death by regulating NAD(+) metabolism (PubMed:27671644). In response to stress, homooligomerizes and catalyzes cleavage of NAD(+) into ADP-D-ribose (ADPR) and nicotinamide; NAD(+) cleavage promoting non-apoptotic neuronal cell death (PubMed:31439792). In males, involved in non-apoptotic death of the linker cell which guides gonad elongation during larval development (PubMed:22363008). Required for both innate immune response and specification of AWC(OFF) neuron (PubMed:15048112, PubMed:15123841, PubMed:15625192). During late embryogenesis, it acts downstream of CAMKII (unc-43) to regulate specification of asymmetric odorant receptors in AWC(OFF) neuron via the nsy-1/ASK1 pmk-1/p38 MAP kinase signaling cascade. Required to localize nsy-1 to postsynaptic regions of AWC neuron, suggesting that it may act by assembling a signaling complex that regulate odorant receptor expression (PubMed:15625192). Also plays a central role in resistance to infection to a broad range of bacterial and fungi pathogens, possibly by activating pmk-1, independently of the NF-kappa-B pathway. Required for expression of antimicrobial peptides nlp-29 and nlp-31 (PubMed:15048112, PubMed:15123841). Its role in immune response and neuron specification may be mediated by the same nsy-1/ASK1 pmk-1/p38 MAP kinase cascade signaling pathway (PubMed:15048112, PubMed:15123841, PubMed:15625192). Involved in the response to anoxic conditions probably by activating the p38 pathway composed of nsy-1/sek-1/pmk-1 (PubMed:21212236). Involved in regulation of the serotonergic response of ADF neurons to pathogenic food (PubMed:23505381). In addition, plays a role in the up-regulation of gcs-1 upon arsenite treatment, most likely through activation of pmk-1, to confer protection against toxicity induced by heavy metals (PubMed:25204677).[1] [2] [3] [4] [5] [6] [7] [8] [9] Regulates expression of antimicrobial peptide nlp-29 in response to fungal infection or physical injury.[10] Publication Abstract from PubMedWallerian axonal degeneration (WD) does not occur in the nematode C. elegans, in contrast to other model animals. However, WD depends on the NADase activity of SARM1, a protein that is also expressed in C. elegans (ceSARM/ceTIR-1). We hypothesized that differences in SARM between species might exist and account for the divergence in WD. We first show that expression of the human (h)SARM1, but not ceTIR-1, in C. elegans neurons is sufficient to confer axon degeneration after nerve injury. Next, we determined the cryoelectron microscopy structure of ceTIR-1 and found that, unlike hSARM1, which exists as an auto-inhibited ring octamer, ceTIR-1 forms a readily active 9-mer. Enzymatically, the NADase activity of ceTIR-1 is substantially weaker (10-fold higher Km) than that of hSARM1, and even when fully active, it falls short of consuming all cellular NAD(+). Our experiments provide insight into the molecular mechanisms and evolution of SARM orthologs and WD across species. Structure-function analysis of ceTIR-1/hSARM1 explains the lack of Wallerian axonal degeneration in C. elegans.,Khazma T, Grossman A, Guez-Haddad J, Feng C, Dabas H, Sain R, Weitman M, Zalk R, Isupov MN, Hammarlund M, Hons M, Opatowsky Y Cell Rep. 2023 Aug 26;42(9):113026. doi: 10.1016/j.celrep.2023.113026. PMID:37635352[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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